HCV currently represents a major public health concern. The number of persons chronically infected with HCV in the world is estimated at 170 million to 200 million and hepatitis-C-related deaths at approximately 470 000 annually. Peak of incidence is expected to occur in 2025-2030 in developed countries.
HCV is a virus that has been implicated in progressive liver diseases such as fibrosis and cirrhosis of the liver and in induction of hepatocellular carcinoma, which are the prime reasons for liver transplants. The prognosis for patients suffering from HCV infection is currently poor. HCV infection is more difficult to treat than other forms of hepatitis due to the lack of immunity or remission associated with HCV infection. Current data indicates a less than 50% survival rate at four years post cirrhosis diagnosis. Patients diagnosed with localized resectable hepatocellular carcinoma have a five-year survival rate of 10-30%, whereas those with localized unresectable hepatocellular carcinoma have a five-year survival rate of less than 1%.
The current standard of care for patients infected with the HCV genotype 1 is a combination of pegylated interferon alpha and ribavirin, a lengthy and often poorly tolerated therapy effective in 50% of patients that complete the therapy. In addition, a substantial number of patients never receive therapy.
Translation of the HCV RNA genome produces an approximately 3000 amino acid polyprotein that contains, from the amino terminus to the carboxy terminus, a nucleocapsid protein (C), envelope proteins (E1 and E2) and several non-structural proteins (P7, NS2, NS3, NS4a, NS4b, NS5a and NS5b).
The NS3 HCV protease necessary for polypeptide processing and viral replication has been identified, cloned and expressed. NS3 is an approximately 68 kda protein, encoded by approximately 1893 nucleotides of the HCV genome, and has two distinct domains: (a) a serine protease domain consisting of approximately 200 of the N-terminal amino acids; and (b) a RNA-dependent ATPase/helicase domain at the C-terminus of the protein.
The NS3 protease is considered a member of the chymotrypsin family because of similarities in protein sequence, overall three-dimensional structure and mechanism of catalysis. Other chymotrypsin-like enzymes are elastase, factor Xa, thrombin, trypsin, plasmin, urokinase, tPA and PSA.
The HCV NS3 protease is responsible for proteolysis of the polypeptide (polyprotein) at the NS3/NS4a, NS4a/NS4b, NS4b/NS5a and NS5a/NS5b junctions and is thus responsible for generating five viral proteins during viral replication. This has made the HCV NS3 protease an attractive target for antiviral chemotherapy. Additionally, the NS4a protein, an approximately 6 kda polypeptide, has been determined to be a co-factor for the protease activity of NS3. Autocleavage of the NS3/NS4a junction by the NS3/NS4a protease occurs intramolecularly (i.e., cis) while the other cleavage sites are processed intermolecularly (i.e., trans).
Analysis of the natural cleavage sites for HCV protease revealed the presence of cysteine at P1 and serine at P1′ and that these residues are strictly conserved in the NS4a/NS4b, NS4b/NS5a and NS5a/NS5b junctions. The NS3/NS4a junction contains a threonine at P1 and a serine at P1′. The Cys-Thr substitution at NS3/NS4a is postulated to account for the requirement of cis rather than trans processing at this junction (see, e.g., Pizzi et al., Proc Natl Acad Sci (USA), 1994, 91(3):888-892; Fulla et al., Fold Des, 1996, 1(1):35-42; Wang et al., J Virol, 2004, 78(2):700-709). The NS3/NS4a cleavage site is also more tolerant of mutagenesis than the other sites (see, e.g., Kolykhalov et al., J Virol, 1994, 68(11):7525-7533). It has also been found that acidic residues in the region upstream of the cleavage site are required for efficient cleavage (see, e.g., Komoda et al., J Virol, 1994, 68(11):7351-7357).
Thus, the conserved portions of the HCV RNA genome are likely targets for effective therapeutic intervention (see, e.g., McCaffrey et al., Hepatology, 2003, 38(2):503-508) using one or more HCV inhibitors.
Inhibitors of HCV protease that have been reported include antioxidants (see, International Patent Publication WO1998/14181), certain peptides and peptide analogs (see, International Patent Publication WO1998/17679, Landro et al., Biochemistry, 1997, 36(31):9340-9348; Ingallinella et al., Biochemistry, 1997, 37(25):8906-89 14; Llinas-Brunet et al., Bioorg Med Chem Lett, 1998, 8(13):1713-1718), inhibitors based on the 70-amino acid polypeptide eglin c (see, Martin et al., Biochemistry, 1998, 37(33):11459-11468), human pancreatic secretory trypsin (hPST1-C3) and minibody repertoire (MBip) inhibitors (see, Dimasi et al., J Virol, 1997, 71(10):7461-7469), antibodies and fragments thereof (such as cVHE2, a “camelized” variable domain antibody fragment) (see, Martin et al., Protein Eng, 1997, 10(5):607-614) and α1-antichymotrypsin (ACT) (see, Elzouki et al., J Hepat, 1997, 27(1):42-48).
Combining various HCV protease inhibitors with an inhibitor of another target in the HCV life cycle including, but not limited to, HCV polymerase inhibitors, NS3 helicase or NS2/NS3 protease inhibitors as well as human immunodeficiency virus (HIV) and hepatitis B virus (HBV) inhibitors has been generally described.
U.S. patent application Ser. No. 12/281,022, filed Feb. 23, 2007 (having corresponding International Patent Application No. PCT/US2007/004721, filed Feb. 23, 2007) describes the use of certain indole and thienopyridine HCV inhibitor compounds and forms thereof in combination with at least one HCV protease inhibitor and, optionally at least one or more additional therapeutic agents, and is incorporated by reference herein in its entirety and for all purposes.
Additional HCV inhibitor compounds and forms thereof in combination with one or more anti-HCV agents have also been disclosed in U.S. patent application Ser. No. 11/653,450, filed Jan. 16, 2007 (having corresponding International Application No. PCT/US2007/00996, filed Jan. 16, 2007) and U.S. patent application Ser. No. 11/653,448, filed Jan. 16, 2007 (having corresponding International Application No. PCT/US2007/00923, filed Jan. 16, 2007), each of which is a continuation-in-part of U.S. patent application Ser. No. 11/331,180, filed Jan. 13, 2006, which is a continuation-in-part of U.S. patent application Ser. No. 11/180,961, filed Jul. 14, 2005 (having corresponding International Application No. PCT/US2005/024881, filed Jul. 14, 2005), each of which is incorporated herein by reference in their entirety and for all purposes.
United States Patent Publication 2006/0235028 discloses certain aryl and heteroaryl compounds as 11-beta-hydroxysteroid dehydrogenase type I inhibitors.
There continues to remain a strong need for new alternative approaches that work through multiple mechanisms of action, including combination products for use in treating or ameliorating HCV infection or disorders or symptoms associated therewith, and that modulate the processivity of viral replication and, in particular, the life cycle of the HCV polypeptide.